Treatment of cancers by chemotherapy or radiotherapy frequently results in side effects because the therapy used is not specific to the cancer and kills non-cancerous cells as well. Where the cancer is resistant to the therapy, the dosage used must be increased, and the side effects become more pronounced. Thus, as a general principal, it would be desirable to be able to increase the sensitivity of cancer cells to chemotherapy and radiotherapy so that lower effective dosages could be employed.
Renal cell cancer (RCC) accounts for approximately 2% of adult carcinomas with over 30,000 new cases and 12,000 deaths per year in the United States. Motzer et al., N. Engl. J. Med. 335: 865-875 (1996). Estimates of annual new diagnoses of RCC have been increasing steadily. Motzer et al, supra; McLaughlin et al., Semin. Oncol. 27: 115-123 (2000). Despite extensive evaluation of many different treatment modalities, advanced metastatic RCC remains highly resistant to systemic therapy. To date, no chemotherapy is established for the treatment of advanced kidney cancer with objective response rates higher than 15% that justifies its use as a single agent. Yagoda et al., Semin. Oncol. 22: 42-60 (1995). Combinations of chemotherapy plus hormonal agents have been studied but likewise are ineffective and result in additive toxicity. Nearly half of all patients with RCC die within 5 years of diagnosis and 5-year-survival for those with metastatic disease is <10%. Motzer et al., J. Urol. 163: 408-417 (2000). Therefore, in order to improve survival, preclinical and clinical evaluation of new agents and treatment programs to identify improved antitumor activity are priorities in this resistant disease.
Bladder cancer is the second most common malignancy of the genitourinary tract, and the fourth or fifth leading cause of cancer-related deaths of men in Western industrialized countries. The prognosis of patients with invasive and/or metastatic bladder cancer is still extremely poor, despite recent therapeutic advances. Advanced bladder cancer is commonly treated with a cisplatin-based combination chemotherapy. However, which palliative efficacy has been observed, this efficacy is limited due to de novo drug resistance or the development of the cellular drug-resistant phenotype during treatment. Thus, advances in the treatment of bladder cancer are desirable.